Nina T. Sherwood, Associate Professor of the Practice

We use Drosophila melanogaster as a model to understand nervous system development and function. A genetic screen for molecules important to these processes identified the fly ortholog of the spastin gene, which when mutated in humans leads to a progressive neurodegenerative disease called Autosomal-Dominant Hereditary Spastic Paraplegia (AD-HSP). Individuals with AD-HSP have difficulty walking, sometimes from as early as childhood, and can end up confined to wheelchairs. We have shown that loss of spastin in the fly larva compromises motoneuron function, while adults exhibit weak legs and do not fly. Spastin is a member of the AAA family of ATPases, and functions by severing microtubules into smaller segments. Our results indicate that the absence of spastin function in mutant flies leads to a reduction in microtubule content at synaptic boutons, presumably causing the weakened neurotransmission. Among our goals in the lab are to understand how this happens at a cell-biological level, and to examine specific phenotypes associated with mutations mimicking those found in the human disease. Using Drosophila as a model system allows us to rapidly generate flies with any number of specific mutations, and then study the consequences of these mutations at the biochemical, cell biological, developmental, electrophysiological and behavioral levels.

Research Categories:Functions of spastin and other microtubule severing proteins in the nervous system; Drosophila models of human disease

Current projects:
Analysis of Drosophila models of human AD-HSP, Genetic screen for candidate interactors of spastin, kat60, or kat-like, Cell biology of microtubule regulation by Spastin and other AAA ATPases, Characterization of Spastin function in other fly tissues/stages, Role of microtubule severing in synaptic bouton formation

Research Description: We use Drosophila melanogaster as a model to understand
nervous system development and function. In a genetic screen
for molecules important to these processes, we discovered the
fly ortholog of the spastin gene, which when mutated in humans
leads to a progressive neurodegenerative disease called
Autosomal-Dominant Hereditary Spastic Paraplegia (AD-HSP).
Individuals with AD-HSP have difficulty walking, sometimes from
as early as childhood, and can end up confined to wheelchairs.
We have shown that loss of spastin in the fly larva compromises
motoneuron function, while adults exhibit weak legs and do not fly.
Spastin is a member of the AAA family of ATPases, and functions
by severing microtubules into smaller segments. This form of
regulation has been shown for only one other protein, katanin,
which is closely related to spastin. Our results indicate that the
absence of such microtubule severing in spastin mutant flies
leads to a reduction in microtubule content at synaptic boutons,
presumably causing the weakened neurotransmission.
Among our goals in the lab are thus to understand how this
happens at a cell-biological level, and to examine specific
phenotypes associated with mutations mimicking those found in
the human disease. Using Drosophila as a model system allows
us to rapidly generate flies with any number of specific spastin
mutations, and then study the consequences of these mutations
at the biochemical, cell biological, developmental,
electrophysiological and behavioral levels.

Areas of Interest:
The role of microtubule severing in the nervous systemRegulation of microtubule severing proteinsDrosophila models of human disease such as AD-HSPMolecular mechanisms of synapse formation